Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
Modified release formulations of gamma-hydroxybutyrate having improved dissolution and pharmacokinetic properties are provided, and therapeutic uses thereof.
1. A pharmaceutical composition that releases gamma-hydroxybutyrate in the blood stream of a human subject, wherein the composition is designed to be administered only once per night, wherein the composition is effective to induce sleep for at least six consecutive hours, and wherein upon administration to a human subject approximately two hours after a standardized evening meal and
at a dose equivalent to 4.5 g or 6.0 g of sodium oxybate, the composition yields a plasma concentration versus time curve bioequivalent to the plasma concentration versus time curve depicted in FIG. 12 for the corresponding dose;
at a dose equivalent to 4.5 g, 6.0 g, or 7.5 g of sodium oxybate, the composition yields a plasma concentration versus time curve bioequivalent to the plasma concentration versus time curve depicted in FIG. 13 for the corresponding dose; or
at a dose equivalent to 4.5 g, 7.5 g, or 9.0 g of sodium oxybate, the composition yields a plasma concentration versus time curve bioequivalent to the plasma concentration versus time curve depicted in FIG. 90 for the corresponding dose.
2. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 7 and FIG. 8 .
3. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 20 and FIG. 21 .
4. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile between the minimum and maximum values depicted in FIG. 25 and FIG. 26 .
5. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile between the minimum and maximum values depicted in FIG. 27 and FIG. 28 .
6. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile between the minimum and maximum values depicted in FIG. 26 and FIG. 28 .
7. The pharmaceutical composition of claim 1 , wherein the composition is defined based on the concentration of gamma-hydroxybutyrate in the blood stream 8 hours after administration to a patient, and further wherein a dose equivalent to a 4.5 g dose of sodium oxybate achieves a mean C 8h of from 4.7 to 9.0 microgram/mL.
8. The pharmaceutical composition of claim 1 , wherein the composition is defined based on the concentration of gamma-hydroxybutyrate in the blood stream 8 hours after administration to a patient, and further wherein a dose equivalent to a 4.5 g dose of sodium oxybate achieves a mean C 8h of from 3.5 to 4.7 microgram/mL.
9. The pharmaceutical composition of claim 1 , wherein the composition is defined based on the concentration of gamma-hydroxybutyrate in the blood stream 8 hours after administration to a patient, and further wherein a dose equivalent to a 6.0 g dose of sodium oxybate achieves a mean C 8h of from 6.3 to 16.7 microgram/mL.
10. The pharmaceutical composition of claim 1 , wherein the composition is defined based on the concentration of gamma-hydroxybutyrate in the blood stream 8 hours after administration to a patient, and further wherein a dose equivalent to a 6.0 g dose of sodium oxybate achieves a mean C 8h of from 7.3 to 15.4 microgram/mL.
11. The pharmaceutical composition of claim 1 , wherein the composition is defined based on the concentration of gamma-hydroxybutyrate in the blood stream 8 hours after administration to a patient, and further wherein a dose equivalent to a 7.5 g dose of sodium oxybate achieves a mean C 8h of from 13.0 to 40.3 microgram/mL.
12. The pharmaceutical composition of claim 1 , wherein the composition is defined based on the concentration of gamma-hydroxybutyrate in the blood stream 8 hours after administration to a patient, and further wherein a dose equivalent to a 7.5 g dose of sodium oxybate achieves a mean C 8h of from 24.7 to 37.2 microgram/mL.
13. The pharmaceutical composition of claim 1 , wherein the composition is defined based on the time required to reach maximum blood concentration of gamma-hydroxybutyrate to a patient, and further achieves a median T max of 1.25 to 3.25 hours when administered once approximately two hours after a standardized evening meal.
14. The pharmaceutical composition of claim 1 , wherein the composition is defined based on the time required to reach maximum blood concentration of gamma-hydroxybutyrate to a patient, and further achieves a median T max of 0.5 to 3.25 hours when administered once approximately two hours after a standardized evening meal.
15. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the dissolution profile depicted in FIG. 29 .
16. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the dissolution profile depicted in FIG. 30 .
17. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the dissolution profile depicted in FIG. 31 .
18. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the dissolution profile depicted in FIG. 32 .
19. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 34 and FIG. 35 .
20. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 37 and FIG. 38 .
21. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 39 and FIG. 40 .
22. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the dissolution profile depicted in FIG. 42 .
23. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 43 and FIG. 44 .
24. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 46 and FIG. 47 .
25. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 49 and FIG. 50 .
26. The pharmaceutical composition of claim 1 , wherein the composition yields a dissolution profile bioequivalent to the dissolution profile depicted in FIG. 53 .
27. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 55 and FIG. 56 .
28. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 58 and FIG. 59 .
29. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 61 and FIG. 62 .
30. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 64 and FIG. 65 .
31. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 66 and FIG. 68 .
32. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 70 and FIG. 71 .
33. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 74 and FIG. 75 .
34. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 77 and FIG. 78 .
35. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 80 and FIG. 81 .
36. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 84 and FIG. 85 .
37. The pharmaceutical composition of claim 1 , wherein the composition yields dissolution profiles bioequivalent to the dissolution profiles depicted in FIG. 88 and FIG. 89 .
38. The pharmaceutical composition of claim 1 , wherein the composition is effective to induce sleep for at least eight consecutive hours.